Project Summary/Abstract Parkinson?s disease (PD)/Parkinson?s disease dementia (PDD) is the second most common chronic, neurodegenerative disorder. It is characterized by the loss of dopaminergic neurons from the substantia nigra, often with extension of pathology into the cortex. The pathogenic mechanism underlying this degeneration remains poorly understood, though analysis of gene products mutated in familial parkinsonisms has contributed to our understanding of PD/PDD pathogenesis. One of these PD-associated gene products, PTEN induced kinase 1 (PINK1), has been shown to prevent cell death induced by parkinsonian injury. However, the mechanisms underlying this protection remain poorly understood. My preliminary data indicate that PINK1 regulates mitochondrial egress from the soma into the dendrites. I have also found that PINK1 regulates phosphorylation of cytoplasmic dynein. These discoveries have led me to hypothesize that PINK1 promotes mitochondrial transport into dendrites by regulating phosphorylation of dynein. I will use advanced microscopic, biochemical, and molecular techniques to determine whether the novel PINK1 regulated phosphorylation of dynein regulates its effects on mitochondrial transport. I will also study the impact of PD-linked PINK1 mutations on dynein phosphorylation and mitochondrial transport. In addition to providing me with predoctoral training, this research proposal will help elucidate mechanisms by which PINK1 regulates mitochondrial distribution in neurons and provide insight into mechanisms underlying PD/PDD pathogenesis.